| RRC ID |
52292
|
| 著者 |
Tsushima H, Morimoto S, Fujishiro M, Yoshida Y, Hayakawa K, Hirai T, Miyashita T, Ikeda K, Yamaji K, Takamori K, Takasaki Y, Sekigawa I, Tamura N.
|
| タイトル |
Kinase inhibitors of the IGF-1R as a potential therapeutic agent for rheumatoid arthritis.
|
| ジャーナル |
Autoimmunity
|
| Abstract |
We have previously shown that the inhibition of connective tissue growth factor (CTGF) is a potential therapeutic strategy against rheumatoid arthritis (RA). CTGF consists of four distinct modules, including the insulin-like growth factor binding protein (IGFBP). In serum, insulin-like growth factors (IGFs) bind IGFBPs, interact with the IGF-1 receptor (IGF-1 R), and regulate anabolic effects and bone metabolism. We investigated the correlation between IGF-1 and the pathogenesis of RA, and the inhibitory effect on osteoclastogenesis and angiogenesis of the small molecular weight kinase inhibitor of the IGF-1 R, NVP-AEW541, against pathogenesis of RA in vitro. Cell proliferation was evaluated by cell count and immunoblotting. The expression of IGF-1 and IGF-1 R was evaluated by RT-PCR. Osteoclastogenesis was evaluated using tartrate-resistant acid phosphatase staining, a bone resorption assay, and osteoclast-specific enzyme production. Angiogenesis was evaluated by a tube formation assay using human umbilical vein endothelial cells (HUVECs). The proliferation of MH7A cells was found to be inhibited in the presence of NVP-AEW541, and the phosphorylation of extracellular signal-regulated kinase (ERK) and Akt was downregulated in MH7A cells. IGF-1 and IGF-1 R mRNA expression levels were upregulated during formation of M-colony stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL)-mediated osteoclast formation. Moreover, osteoclastogenesis was suppressed in the presence of NVP-AEW541. The formation of the tubular network was enhanced by IGF-1, and this effect was neutralized by NVP-ARE541. Our findings suggest that NVP-AEW541 may be utilized as a potential therapeutic agent in the treatment of RA.
|
| 巻・号 |
50(5)
|
| ページ |
329-335
|
| 公開日 |
2017-8-1
|
| DOI |
10.1080/08916934.2017.1344970
|
| PMID |
28682648
|
| MeSH |
Animals
Antirheumatic Agents / pharmacology*
Antirheumatic Agents / therapeutic use
Arthritis, Rheumatoid / drug therapy
Arthritis, Rheumatoid / metabolism*
Arthritis, Rheumatoid / pathology
Cell Line
Cell Proliferation / drug effects
Female
Humans
Insulin-Like Growth Factor I / metabolism
Insulin-Like Growth Factor I / pharmacology
Macrophage Colony-Stimulating Factor / metabolism
Macrophage Colony-Stimulating Factor / pharmacology
Mice
Neovascularization, Pathologic / metabolism
Osteoclasts / cytology
Osteoclasts / drug effects
Osteoclasts / metabolism
Protein Kinase Inhibitors / pharmacology*
Protein Kinase Inhibitors / therapeutic use
Pyrimidines / pharmacology
Pyrroles / pharmacology
RANK Ligand / metabolism
RANK Ligand / pharmacology
Receptor, IGF Type 1
Receptors, Somatomedin / antagonists & inhibitors*
Receptors, Somatomedin / metabolism*
Signal Transduction / drug effects
|
| IF |
2.125
|
| 引用数 |
3
|
| リソース情報 |
| ヒト・動物細胞 |
MH7A(RCB1512) |
